{"doi":"10.1101/2025.06.25.25330124","title":"Complexome profiling showed impaired immunoproteasome assembly in a novel PRAAS subtype caused by monoallelic PSMB8 variants","abstract":"Abstract Immunoproteasomes, essential for MHC class I antigen presentation, differ from standard proteasomes by incorporating the catalytic subunits PSMB9 (β1i), PSMB10 (β2i), and PSMB8 (β5i). Proteasome-associated autoinflammatory syndromes (PRAAS) are type I interferonopathies resulting from impaired proteasome function. Here, we describe two individuals carrying monoallelic de novo variants in PSMB8 , both presenting with early-onset systemic autoinflammation and features of immunodeficiency, accompanied by a marked type I interferon response. To investigate the underlying mechanism, we performed complexome profiling on interferon-γ-stimulated fibroblasts harboring the p.(Ala235Asp) variant. This variant, located at the β-ring interface, disrupted proper assembly of the immunoproteasome, resulting in reduced levels of fully assembled 20S and 26S immunoproteasomes and accumulation of assembly intermediates. The findings suggest a dominant-negative effect and broaden the clinical and genetic spectrum of PRAAS with immunodeficiency (PRAAS-ID), while highlighting the utility of complexome profiling to study proteasome assembly defects.","journal":"medRxiv","year":2025,"id":558331,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":623102,"name":"Caspar I. van der Made","orcid":"0000-0003-0763-4017","position":1,"is_corresponding":false},{"id":1459214,"name":"Sema Kalkan Uçar","orcid":null,"position":2,"is_corresponding":false},{"id":1172122,"name":"Gayatri Ramakrishnan","orcid":"0000-0001-8203-2783","position":3,"is_corresponding":false},{"id":15091,"name":"Jill A. Rosenfeld","orcid":"0000-0001-5664-7987","position":4,"is_corresponding":false},{"id":254732,"name":"Tiphanie P. Vogel","orcid":"0000-0002-0857-133X","position":5,"is_corresponding":false},{"id":354476,"name":"Sarah K. Nicholas","orcid":"0000-0003-2163-9607","position":6,"is_corresponding":false},{"id":740563,"name":"Monika Weisz‐Hubshman","orcid":null,"position":7,"is_corresponding":false},{"id":276384,"name":"Undiagnosed Diseases Network","orcid":null,"position":8,"is_corresponding":false},{"id":1284230,"name":"Alfredo Cabrera‐Orefice","orcid":"0000-0002-2042-3794","position":9,"is_corresponding":false},{"id":1214635,"name":"Bente Siebels","orcid":"0000-0001-9183-0381","position":10,"is_corresponding":false},{"id":1459215,"name":"Thomas Mair","orcid":null,"position":11,"is_corresponding":false},{"id":1009626,"name":"Hartmut Schlüter","orcid":"0000-0002-9358-7036","position":12,"is_corresponding":false},{"id":1459216,"name":"Ruben L. Smeets","orcid":null,"position":13,"is_corresponding":false},{"id":1311698,"name":"Ronald van Beek","orcid":null,"position":14,"is_corresponding":false},{"id":733472,"name":"Clara D.M. van Karnebeek","orcid":"0000-0002-2648-8337","position":15,"is_corresponding":false},{"id":57009,"name":"Alexander Hoischen","orcid":"0000-0002-8072-4476","position":16,"is_corresponding":false},{"id":633062,"name":"Lisenka E.L.M. Vissers","orcid":"0000-0001-6470-5497","position":17,"is_corresponding":false},{"id":331218,"name":"Saskia B. Wortmann","orcid":"0000-0002-1968-8103","position":18,"is_corresponding":false},{"id":293132,"name":"Ron A. Wevers","orcid":"0000-0003-2278-9746","position":19,"is_corresponding":false},{"id":1082498,"name":"Machteld M. Oud","orcid":"0000-0003-4864-9346","position":20,"is_corresponding":false},{"id":447355,"name":"Sergio Guerrero‐Castillo","orcid":"0000-0002-6630-0562","position":21,"is_corresponding":false},{"id":1311697,"name":"Robin Wijngaard","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40666351","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}